Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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1
NOVEL MANUFACTURING METHOD OF DAPRODUSTAT AND PRECURSORS THEREOF
FIELD OF THE INVENTION
The present disclosure relates to a manufacturing process for daprodustat in
which the level of an
acyl impurity of Formula (II) is kept below 0.15% w/w in isolated daprodustat
drug substance.
Immediate release formulations of daprodustat containing a composition of
daprodustat in which the
level of the acyl impurity of Formula (II) is kept below 0.15% w/w relative to
daprodustat drug
substance are also disclosed. Medical uses of the immediate release
formulation and dosage regimens
are disclosed.
BACKGROUND TO THE INVENTION
Impurities can arise during the manufacturing process and/or storage of new
drug substances.
These include starting materials, intermediates, by-products, degradation
products and reagents
ligands and catalysts.
Given that impurities can produce pharmacological or toxic effects, each
impurity identified by a
manufacturer must be kept below a threshold level, termed its acceptance
criteria. The acceptance
criteria for a particular impurity reflects the effects associated with that
impurity.
It is a regulatory requirement to produce a specification for a new drug
substance. This must
specify the acceptance criteria for identified impurities, the acceptance
criteria for unspecified
impurities and the acceptance criteria for total impurities.
Daprodustat is a prolyl hydroxylase inhibitor that is currently in development
for the treatment of
anemia due to chronic kidney disease. Daprodustat is the USAN, INN and JAN
name for the
compound N-(0,3-theydohezylhexahydro-2,4,6-trioxopyrfrnidirt-5-
0,carbonyDalycine . Small scale
laboratory synthesis of daprodustat is disclosed in W02007/150011.
SUMMARY OF THE INVENTION
In a first aspect, the invention provides a process for preparing 1,3-
dicyclohexylpyrimidine-
2,4,6(1H,3H,5H)-trione comprising reacting 1,3-dicyclohexylurea with malonic
acid, wherein the
products of the reaction are 1,3-dicyclohewlpyrimidine-2,4,6(1H,3H,5H)-trione
and a compound of
formula (II)
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2
NN
oo
(7)1.21
(II)
wherein R1 is C1_6a1lcy1,wherein the solvent system is selected to maintain
the compound of formula
(II) in solution at the temperature at which 1,3-dicyclohexylpyrimidine-
2,4,6(1H,3H,5H)-trione is
isolated, and wherein the reaction is terminated before the concentration of
formula (II) exceeds its
solubility in the solvent system employed.
In a second aspect, the invention provides a process for preparing N-[(1,3-
dicyclohexy1-6-hydroxy-
2,4-clioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine or a
pharmaceutically acceptable salt
thereof, comprising a step of preparing 1,3-dicyclohexylpyrimidine-
2,4,6(1H,3H,5H)-trione as
defined herein.
In a third aspect, the invention provides a composition of N-[(1,3-
dicyclohexyl-6-hydroxy-2,4-dioxo-
1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine or a pharmaceutically
acceptable salt thereof,
wherein N-[(1,3-dicyclohexy1-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-
pyrimidinyl)carbonyl]glycine
or a pharmaceutically acceptable salt thereof is obtained according to a
process as defined herein.
In a fouth aspect, the invention provides a process for preparing an immediate
release formulation
of N-[(1,3-dicyclohexy1-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-
pyrimidinyl)carbonyl]glycine or a
pharmaceutically acceptable salt thereof, comprising a step of preparing N-
[(1,3-dicyclohexy1-6-
hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine or a
pharmaceutically
acceptable salt thereof as defined herein.
In a fifth aspect, the invention provides an immediate release formulation of
N-[(1,3-dicyclohexy1-6-
hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine or a
pharmaceutically
acceptable salt thereof, comprising a composition of N-[(1,3-dicyclohexy1-6-
hydrow-2,4-dioxo-
1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine or a pharmaceutically
acceptable salt thereof
which composition comprises less than 0.15% w/w of a compound of formula (II)
or a
pharmaceutically acceptable salt thereof relative to daprodustat drug
substance .
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In a sixth aspect, the invention provides a compound of formula (II) or a
pharmaceutically acceptable
salt thereof:
[a e.....".***Nr...10
Ci.....--.s..'*--LO
01R1
(II)
wherein RI. is Ci-olkyl.
In one particular embodiment, the invention provides a compound that is 5-
acety1-1,3-
dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione.
In further aspects, the invention provides medical uses of the immediate
release formulation defined
herein.
DESCRIPTION OF DRAWINGS/FIGURES
FIG. 1 shows the effect of imidazole (0.5% w/w) on progress of the Stage 1
reaction. Figure IA
shows the rate of intermediate consumption. Figure 113
shows the rate of product (1,3-
dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione) formation. Figure IC shows the
rate of formation of
1,3-dicyclohexy1-2H-pyrano[2,3-d]pyrimidine-2,4,5,7(1H,3H,6H)-tetraone and
Figure 1D shows the
rate of formation of 5-acetyl-1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-
trione. Solid lines show the
reaction rate in the presence of the imidazole additive. Dashed lines show the
reaction rate without
additive.
FIG. 2 shows the effect of effect of /V,N-dimethylaminopyridine (0.9% w/w;
equivalent to 1.65 mol
% relative to /V,N-dicyclohexylurea) on progress of the Stage 1 reaction.
Figure 2A shows the rate of
intermediate consumption. Figure 2B shows the rate of product (1,3-
dicyclohexylpyrimidine-
2,4,6(1H,3H,5H)-trione) formation. Figure 2C shows the rate of formation of
1,3-dicyclohexy1-2H-
pyrano[2,3-d]pyrimidine-2,4,5,7(1H,3H,6H)-tetraone and Figure 2D shows the
rate of formation of 5-
acety1-1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione. Solid lines show the
reaction rate in the
presence of the imidazole additive. Dashed lines show the reaction rate
without additive.
FIG. 3 shows the effect of varying amounts (in %w/w) of imidazole in /V,N-
dicyclohexylurea on
progress of the Stage 1 reaction. Figure 3A shows the rate of intermediate
consumption. Figure 3B
shows the rate of product (1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione)
formation. Figure 3C
shows the rate of formation of 1,3-dicyclohexy1-2H-pyrano[2,3-d]pyrimidine-
2,4,5,7(1H,3H,6H)-
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tetraone and Figure 3D shows the rate of formation of 5-acety1-1,3-
dicyclohexylpyrimidine-
2,4,6(1H,3H,5H)-trione. Solid lines show the reaction rate in the presence of
the imidazole additive.
Dashed lines show the reaction rate without additive.
FIG 4 is a Half-Normal Plot summarizing the model for the rate of formation of
5-acetyl-1,3-
dicyclohex),/lpyrimidine-2,4,6(1H,3H,5H)-trione. CD show the combined effects
of imidazole and
quantity of acetic acid and CE shows the combined effect of imidazole and
reaction temperature.
FIGS 5A and B are interaction plots. Figure 5A shows the effect of the amount
(in Tow/w) of imidazole
in /V,ff-dicyclohexylurea upon the initial rate of formation of 5-acety1-1,3-
dicyclohexylpyrimidine-
2,4,6(1H,3H,5H)-trione of in the presence of 2 volumes acetic acid (squares)
and 4 volumes of acetic
acid (triangles). Figure 5B shows the effect of the amount (in Vow/w) of
imidazole in /V,Ar-
dicyclohexylurea upon the initial rate of formation of 5-acety1-1,3-
dicyclohexylpyrimidine-
2,4,6(1H,3H,5H)-trione at reaction temperatures of 50 C (squares) and 60 C
(triangles).
DETAILED DESCRIPTION OF THE INVENTION
MANUFACTURE
Daprodustat is the USAN, INN and JAN name for the compound N-((1.3-
clicyclohexylnexariydro-2,4,6-
tiioxopyrii-oidin-5-yl)cad.)onyi)glycine (the IUPAC name for this compound is
A/4(1,3-
Dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5-yl)carbonyl]glycine).
Daprodustat exhibits keto/enol
tautomerism and can also be named N-[(1,3-dicyclohexy1-6-hydroxy-2,4-dioxo-
1,2,3,4-tetra hydro-5-
pyrimidinyl)carbonyl]g lycine. Where claims refer to N-[(1,3-dicyclohexy1-6-
hydroxy-2,4-dioxo-1,2,3,4-
tetrahydro-5-pyrimidinyl)carbonyl]glycine, all tautomers of N-[(1,3-
dicyclohexy1-6-hydroxy-2,4-dioxo-
1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine, including mixtures thereof,
are intended to be
encompassed within the scope of the invention.
The free acid and metal salts of daprodustat may be manufactured according to
the general synthetic
scheme shown below:
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0 0
0 a
H0)...'")-.....*0 H
Stage 1
H H
0 0
Stage 2a Iiir 0
OCN,....,..)L
P1
(III)
-'
9 9
0,.õ......õ N,.................õ.0H Stage 2b, c
0,......,õ N .....,...õ...õõOH
0 -r4_ 0
kil H
ciN.,_. N ....õ..,.....,....,-...........,....õ,,N ,,............,,,,,
P1
0 [Metal+1
0 0 a 0 0
Stage 3
Illr,
9
cm ti...,,,,..........õ...N 0H
0
H
ci, N
0 0
wherein P1 is a suitable protecting group, such as C1-6a1ky1, benzyl or vinyl.
The reaction of Stage 1 requires the use of a dehydrating agent, for example a
compound of formula
5 (I):
0 0
R1).V.......-...R2
Wherein 121 is C1-6a1ky1 and R2 is C1-6alkyl.
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In addition to the desired reaction in Stage 1, a side reaction occurs leading
to the production of an
acyl impurity of formula (II):
a Nr.'-....".. e...C1
0......'L.0
(II)
Additionally, the impurity of formula (II) may be generated in Stage 1 and
Stage 2 by reaction with a
carboxylic acid of formula R1CO2H, where this carboxylic acid is present (e.g.
as a solvent).
In one embodiment, R1 is methyl, such that the compound of formula (II) is 5-
acetyl-1,3-
dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione.
As demonstrated in Example 1, the impurity of Formula (II) is not readily
purged in Stages 2 and 3
of the process. Example 4 teaches that, where the concentration of the
impurity of Formula (II) is
below its solubility in the solvent system employed in Stage 1, the impurity
can be purged
effectively. Example 4, specifically demonstrates purging of a compound of
formula (II) that is 5-
acetyl-1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione. 5-Acetyl-1,3-
dicyclohexylpyrimidine-
2,4,6(1H,3H,5H)-trione has a solubility of 43.7 mg/ml in 29.5 /ov/v acetic
anhydride¨acetic acid (the
solvent system employed for Stage 1 in example 4) at 15 C (the isolation
temperature used in
Example 4). The experiment in Example 4 demonstrated that 45.2 mg/ml 5-acetyl-
1,3-
dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione could be completely purged
during isolation of the
product of Stage 1. In other words, complete purging was observed where the
concentration of 5-
acetyl-1,3-dicyclohenflpyrimidine-2,4,6(1H,3H,5H)-trione approximates the
solubility of this
compound in the solvent system at the isolation temperature.
The skilled person would expect other compounds of formula (II) to be purged
during isolation of the
product of Stage 1 in the situation where (as in Example 4) they are
substantially dissolved in the
solvent system. In other words, the skilled person would realise that the
concentration of the
compound of Formula (II) at the time the reaction is terminated must be no
greater than the solubility
limit for the solvent system at the isolation temperature. In view of this,
the skilled reader would
appreciate the necessity of terminating the reaction whilst the concentration
of the compound of
formula (II) was below the solubility limit for the solvent system at the
isolation temperature.
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Accordingly, in a first aspect, the invention provides a process for preparing
1,3-
dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione comprising reacting 1,3-
dicyclohexylurea with ma Ionic
acid, wherein the products of the reaction are 1,3-dicyclohexylpyrimidine-
2,4,6(1H,3H,5H)-trione
and a compound of formula (II)
CL-e.......'N.' N"......-0
00
01R1
(II)
wherein R1 is Ci_6alkyl,wherein the solvent system is selected to maintain the
compound of formula
(II) in solution at the temperature at which 1,3-dicyclohexylpyrimidine-
2,4,6(1H,3H,5H)-trione is
isolated, and wherein the reaction is terminated before the concentration of
formula (II) exceeds its
solubility in the solvent system employed.
It will be apparent that the point at which the reaction is terminated will
depend upon both the
compound of formula (II), the solvent system employed and the isolation
temperature selected.
Where the compound of formula (II) is 5-acetyl-1,3-dicyclohexylpyrimidine-
2,4,6(1H,3H,5H)-trione,
the solvent system is 29.5 /oviv acetic anhydride¨acetic acid, and the
isolation temperature is 15 C,
the reaction should be terminated before the concentration of 5-acetyl-1,3-
dicyclohexylpyrimidine-
2,4,6(1H,3H,5H)-trione is 45.2 mg/ml.
Solubility studies such as those described in Example 4 can be used to
determine the point at which
the reaction is terminated for any particular compound of formula (II),
solvent system and isolation
temperature.
HPLC can be used to monitor reaction progress. Detection at 210 nm can be used
to detect both
the product of Stage 1 and the compound of formula (II). As shown in Example
4, 1,3-
dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione was completely purged when the %
area by HPLC was
45.6. Accordingly, HPLC monitoring can be used as an alternative to monitoring
concentration of 5-
acetyl-1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione to identify the point
at which the reaction
of Stage 1 should be terminated.
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In one embodiment where the compound of formula (II) is 5-acetyl-1,3-
dicyclohexylpyrimidine-
2,4,6(1H,3H,5H)-trione and the reaction conditions used to prepare 1,3-
dicyclohexylpyrimidine-
2,4,6(1H,3H,5H)-trione and 5-acetyl-1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-
trione used 1,3-
dicyclohex),/lurea (1.0 wt), malonic acid (1.3 wt), acetic acid (2.7 wt) and
acetic anhydride (6.6 eq)
and the isolation temperature is 15 C, the reaction should be terminated
before the percentage of 5-
acetyl-1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione exceeds 45% by area
of the products of the
reaction. HPLC monitoring can be used to identify the point at which the
reaction of Stage 1 should
be terminated for other compounds of formula (II). The percentage by area of
the compound of
formula (II) when this is sufficiently dissolved in the appropriate solvent
system can readily be
determined by HPLC. Where the concentration of the compound of formula (II) is
at its solubility limit
for the solvent system and isolation temperature, this percentage by area
approximates the point at
which the Stage 1 reaction should be terminated.
The Stage 1 reaction takes place in the presence of a suitable solvent system.
The solvent system is
selected to maintain the compound of formula (II) in solution and the product
of the Stage 1
reaction (1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione) substantially not
in solution at the
temperature at which 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione is
isolated, such that the
compound of formula (II) can be removed by filtration (in the filtrate). In
one embodiment, the
solvent is a mixture of a carboxylic acid of formula R1CO2H. The dehydrating
agent of formula (I)
may also form part of the solvent system. In one embodiment, the solvent
system is a mixture of
acetic acid and the dehydrating agent, acetic anhydride.
The reaction may be terminated by any convenient method. In one embodiment,
the reaction is
mixture is cooled, for example to 15-25 C. In another embodiment, the reaction
is terminated by
filtration. Filtration terminates the reaction by removal of starting
materials and impurities
(including the compound of formula II), and results in a filter cake. The
filter cake may be washed
to purify the product of the reaction and to remove traces of solvents that
are incompatible with
subsequent steps or which lead to undesirable side reactions, for example side
reactions leading to
the compound of formula (II).
In a particular embodiment, where a carboxylic acid of formula 111.0O2H is
used in Stage 1, the filter
cake is washed to reduce the levels of this carboxylic acid to not greater
than 0.1% (w/w). Levels
of the carboxylic acid of formula R1CO2H may be measured by gas
chromatography. Calibration
may be used to covert a gas chromatography peak for the carboxylic acid of
formula FOCO2H to its
weight. In a particular embodiment, the filter cake is washed with a solvent
in which the compound
of formula (II) significantly more soluble than 1,3-dicyclohexylpyrimidine-
2,4,6(1H,3H,5H)-trione at
the temperature employed. Washes may also be employed simply to displace other
solvents.
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In one embodiment, the filter cake is washed with not less than 2 volumes of a
solvent other than a
carboxylic acid of formula R1CO2H.
In a particular embodiment in which the compound of formula (II) is 5-acetyl-
1,3-
dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione, the solvent system is 29.5%v/v
acetic anhydride¨
acetic acid, and the isolation temperature is 15 C, the filter cake is washed
with 2 volumes acetic
acid and 2 volumes water. The first wash is used to displace the reaction
liquors in the filter
equipment, and the second wash is used to displace the acetic acid.
This invention teaches how to control the compound of formula (II) in the
final product,
daprodustat. As described above, the key control is to terminate the Stage 1
reaction at a point at
which the compound of formula (II) can be effectively purged. By meeting this,
the compound of
formula (II) will not appear in daprodustat drug substance above the 0.15%
threshold set by
regulatory authorities.
In addition to this, the inventors have identified how to limit the production
of the compound of
formula (II). It will be appreciated that, by reducing the production of the
compound in formula (II)
in Stage 1, a greater yield of the product can be achieved before the reaction
must be terminated.
Specifically, the inventors have identified that the product specification of
the starting material 1,3-
dicyclohex),/lurea and in particular the content of imidazole in the starting
material has major impact
on the production of the compound of formula (II). Imidazole is a by-product
of the manufacturing
process for 1,3-dicyclohexylurea starting from N,N'-carbonyldiimidazole. It is
purged during Stage 1,
but also catalyses the formation of the compound of formula (II). Examples 2
and 3 demonstrate
that the imidazole content of the starting material 1,3-dicyclohexylurea has a
significant impact upon
the level of the compound of formula (II) after Stage 1. Accordingly, in one
embodiment the the
1,3-dicyclohexylurea starting material contains not greater than 0.05 % (w/w)
imidazole. Whilst a
small effect on formation of the compound of formula (II) is observed with
this level of imidazole,
reduction of the imidazole content below this level is practically difficult
to achieve for suppliers.
Additionally, the inventors identified an impact of the Stage 1 reaction
temperature upon the rate of
formulation of the compound of formula (II). In one embodiment, the Stage 1
reaction is
conducted at a temperature between 50-60 C. In a more particular embodiment,
the Stage 1
reaction is conducted at 50 C.
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In one aspect, the invention provides a process for preparing N-[(1,3-
dicyclohexy1-6-hydroxy-2,4-
dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine or a pharmaceutically
acceptable salt thereof
comprising a step of preparing 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-
trione as defined herein.
5 Subsequent steps of the process may be conducted as shown in general
synthetic scheme shown
above.
Stage 2a comprises reaction with a compound of formula (III) such as ethyl 2-
isocyanatoacetate
in the presence of a suitable base such as triethylamine in a suitable solvent
such as
10 tetrahydrofuran.
Stage 2b comprises reaction with a metal hydroxide to form the appropriate
salt. For example,
treatment with aqueous potassium hydroxide results in the formation of the
potassium salt.
Treatment with aqueous sodium hydroxide results in formation of the sodium
salt.
Stage 2c is an evaporation step aimed at reducing levels of solvents used in
earlier stages, e.g.
tetrahydrofuran.
Stage 3 comprises treatment with an acid, such as aqueous hydrochloric acid in
a suitable solvent
such as acetone.
Example 1 describes the impact of acetic acid in Stage 2 upon the levels of 5-
acety1-1,3-
dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione in daprodustat. Table 4 showed
that levels of 0.1%
acetic acid can be tolerated in Stage 2. Accordingly, in one embodiment, the
levels of a carboxylic
acid of formula R1CO2H in 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione
are less than or equal
to 0.1% (w/w) immediately prior to reaction with a compound of formula (III).
In one embodiment, the product of the process is a pharmaceutically acceptable
salt of N-[(1,3-
dicyclohexy1-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]g
lycine.
In one embodiment, the product of the process is N-[(1,3-dicyclohexy1-6-
hydroxy-2,4-dioxo-1,2,3,4-
tetrahydro-5-pyrimidinyl)carbonyl]glycine free acid.
In one embodiment, the product of the process (N-[(1,3-dicyclohexy1-6-hydroxy-
2,4-dioxo-1,2,3,4-
tetrahydro-5-pyrimidinyl)carbonyl]glycine or a pharmaceutically acceptable
salt thereof) is in
crystalline form.
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In one embodiment, the product of the process (N-[(1,3-dicyclohexy1-6-hydroxy-
2,4-dioxo-1,2,3,4-
tetrahydro-5-pyrimidinyl)carbonyl]glycine free acid is in crystalline form.
In a particular embodiment, the product of the process (N-[(1,3-dicyclohexy1-6-
hydroxy-2,4-dioxo-
1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine free acid is a non-solvated
crystalline form referred
to as CS1. Form CS1 has an X-ray powder diffraction pattern that has
characteristic peaks at 2theta
values of 6.4 0.2 , 7.5 0.2 , and 7.9 0.2 using CuKa radiation. In a more
particular
embodiment, the X-ray powder diffraction pattern of form CS1 has one or more
additional
characteristic peaks at 2theta values of 17.2 0.2 , 21.00 0.20, 24.00 0.20,
and 19.3 0.2
using CuKa radiation. Form CS1 has an endothermic peak at around 242 C as
measured by
differential scanning calorimetry using a heating rate of 10 C min and a purge
gas of nitrogen.
In another embodiment, the product of the process (N-[(1,3-dicyclohexy1-6-
hydroxy-2,4-dioxo-
1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine free acid is a non-solvated
crystalline form referred
to as CS9. Form CS9 has an X-ray powder diffraction pattern that has
characteristic peaks at 2theta
values of 4.6 0.2 , 6.6 0.2 , and 21.1 0.2 using CuKa radiation. In a more
particular
embodiment, the X-ray powder diffraction pattern for form CS9 has one or more
additional
characteristic peaks at 2theta values of 9.4 0.2 , 20.2 0.2 , and 24.2 0.2
using CuKa radiation.
Forms CS1 and CS9 may be crystallised from the free acid according to
processes described in
W02019052133.
In another embodiment, the product of the process (N-[(1,3-dicyclohexy1-6-
hydroxy-2,4-dioxo-
1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine free acid is a crystalline
form referred to as Form 3.
Form 3 has an X-ray powder diffraction pattern having peaks at 2-theta values
of 4.5 0.2 ,
5.6 0.2 , 9.0 0.2 and 16.8 0.2 using CuKa radiation. In a more particular
embodiment, the
X-ray powder diffraction pattern of Form 3 has one or more additional
characteristic peaks at 2-
theta values selected from 8.5 0.2 , 11.2 0.2 , 20.6 0.2 and 24.7 0.2
using CuKa radiation
and/or a DSC endothermic peak with T onset at about 245.3 C.
In another embodiment, the product of the process (N-[(1,3-dicyclohexy1-6-
hydroxy-2,4-dioxo-
1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine free acid is a crystalline
form referred to as Form
4. Form 4 has an X-ray powder diffraction pattern having peaks at 2-theta
values of 7.2 0.2 ,
11.5 0.2 , 21.7 0.2 , 22.9 0.2 , 23.3 0.2 and 25.8 0.2 using CuKa
radiation. In a more
particular embodiment, the X-ray powder diffraction pattern of Form 4 has one
or more additional
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characteristic peaks at 2-theta values selected from 6.3 0.2 , 12.9 0.2 ,
16.5 0.2 ,
18.1 0.2 and 19.7 0.2 using CuKa radiation, and/or a DSC endothermic peak
with T onset at
about 243.9 C.
Forms 3 and 4 may be crystallised as described in W02020102302.
In another embodiment, the product of the process (N-[(1,3-dicyclohexy1-6-
hydroxy-2,4-dioxo-
1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine free acid is a crystalline
form referred to as form M.
Form M has an X-ray powder diffraction pattern that has characteristic peaks
at 2theta values of
4.7 0.2 , 6.5 0.2 , and 6.8 0.2 using CuKa radiation. Form M may be
crystallised as
described in W02021031102.
In one aspect, the invention provides a composition of N-[(1,3-dicyclohexy1-6-
hydroxy-2,4-dioxo-
1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine or a pharmaceutically
acceptable salt thereof,
wherein N-[(1,3-dicyclohexy1-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimid
inyl)carbonyl]glycine
or a pharmaceutically acceptable salt thereof is obtained according to a
process described herein. In
a related aspect, the invention provides a composition of N-[(1,3-dicyclohexy1-
6-hydroxy-2,4-dioxo-
1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine or a pharmaceutically
acceptable salt thereof,
which composition comprises less than 0.15% w/w of the compound of formula
(II) or a
pharmaceutically acceptable salt thereof. In one embodiment, the composition
comprises between
0.01-0.15% w/w of the compound of formula (II) or a pharmaceutically
acceptable salt thereof.
In another aspect, the invention provides a compound of formula (II) or a
pharmaceutically acceptable
salt thereof:
ca 0 ....,0
N N
0"0
(:).\,.µw
(II)
wherein R1 is C1-6.alkyl.
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In one embodiment, R1 is methyl in the compound of formula (II) or a
pharmaceutically acceptable
salt thereof.
In one embodiment, the invention provides a compound that is: 5-acety1-1,3-
dicyclohexylpyrimidine-
2,4,6(1H,3H,5H)-trione.
The compound of formula (II) exhibits keto/enol tautomerism and the specific
compound of formula
(II) that is 5-acety1-1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione can
also be named 5-acetyl-
1,3-dicyclohexy1-6-hydroxypyrimidine-2,4(1H,3H)-dione. Where claims refer to a
compound of
formula (II) or 5-acetyl-1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione,
all tautomers, including
mixtures thereof, are intended to be encompassed within the scope of the
invention.
PHARMACEUTICAL COMPOSITIONS
In another aspect, the invention provides a process for preparing an immediate
release formulation
of N-[(1,3-dicyclohexy1-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-
pyrimidinyl)carbonyl]glycine or a
pharmaceutically acceptable salt thereof, comprising a step of preparing N-
[(1,3-dicyclohexy1-6-
hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine or a
pharmaceutically
acceptable salt thereof as defined herein. In one embodiment, said N-[(1,3-
dicyclohexy1-6-hydroxy-
2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine or a
pharmaceutically acceptable salt
thereof is N-[(1,3-dicyclohexy1-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-
pyrimidinyl)carbonyl]glycine free acid. In a more particular embodiment, N-
[(1,3-dicyclohexy1-6-
hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine free acid
is in crystalline form.
In an alternative embodiment, said N-[(1,3-dicyclohexy1-6-hydroxy-2,4-dioxo-
1,2,3,4-tetrahydro-5-
pyrimidinyl)carbonyl]glycine or a pharmaceutically acceptable salt thereof is
a pharmaceutically
acceptable salt of N-[(1,3-dicyclohexy1-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-
5-
pyrimidinyl)carbonyl]glycine, for example the sodium or potassium salt.
In another aspect, the invention provides an immediate release formulation of
N-[(1,3-dicyclohexy1-
6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine or a
pharmaceutically
acceptable salt thereof obtained by a process described herein.
In one aspect, the invention provides an immediate release formulation of N-
[(1,3-dicyclohexy1-6-
hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine or a
pharmaceutically
acceptable salt thereof, comprising a composition of N-[(1,3-dicyclohexy1-6-
hydroxy-2,4-dioxo-
1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine or a pharmaceutically
acceptable salt thereof
which composition comprises less than 0.15 /0 w/w of a compound of formula
(II) or a
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pharmaceutically acceptable salt thereof, relative to levels of N-[(1,3-
dicyclohexy1-6-hydroxy-2,4-
dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine or a pharmaceutically
acceptable salt
thereof.
In one aspect, the immediate release formulation of the invention comprises a
composition of N-
[(1,3-dicyclohex1,11-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-
pyrimidinyl)carbonyl]glycine or a
pharmaceutically acceptable salt thereof which composition comprises less than
0.15% w/w of a
compound of formula (II) or a pharmaceutically acceptable salt thereof.
In one embodiment, the immediate release formulation of the invention
comprises between 0.01-
0.15% /w of a compound of formula (II) or a pharmaceutically acceptable salt
thereof.
In one embodiment, the compound of formula (II) or a pharmaceutically
acceptable salt thereof is 5-
acety1-1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione or a pharmaceutically
acceptable salt
thereof. In one embodiment, the compound of formula (II) or a pharmaceutically
acceptable salt
thereof is 5-acetyl-1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione.
In one embodiment, the immediate release formulation of the invention is a
tablet.
In one embodiment, an immediate release tablet of N-[(1,3-dicyclohexy1-6-
hydroxy-2,4-dioxo-1,2,3,4-
tetrahydro-5-pyrimidinyl)carbonyl]glycine or a pharmaceutically acceptable
salt thereof is a tablet
comprising from 1 to 8 mg (measured as the free acid) of N-[(1,3-dicyclohexy1-
6-hydroxy-2,4-dioxo-
1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine or a pharmaceutically
acceptable salt thereof that
meets the following dissolution criteria:
1. A mean (based on at least 12 tablets) of 85% or more of the of N-[(1,3-
dicyclohen4-6-
hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine free acid
contained in
the tablet dissolves within 45 minutes or less using United States
Pharmacopeia (USP)
Apparatus 2 with a rotational speed of 50 2 rpm and a dissolution volume of
500 5 mL
for tablets containing <2 mg of N-[(1,3-dicyclohexy1-6-hydroxy-2,4-dioxo-
1,2,3,4-tetra hyd ro-
5-pyrimidinyl)carbonyl]glycine or a pharmaceutically acceptable salt thereof
(measured as the
free acid) and 900 9 mL for tablets containing
mg of N-[(1,3-dicyclohexy1-6-hydroxy-
2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine or a
pharmaceutically acceptable
salt thereof (measured as the free acid) in a pH 6.8 buffer or Simulated
Intestinal Fluid USP
without enzymes.
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In one embodiment, the dissolution profile of an immediate release tablet
comprising from 1 to 8 mg
(measured as the free acid) of N-[(1,3-dicyclohexy1-6-hydroxy-2,4-dioxo-
1,2,3,4-tetrahydro-5-
pyrimidinyl)carbonyl]glycine or a pharmaceutically acceptable salt thereof or
a pharmaceutically
acceptable salt thereof using United States Pharmacopeia (USP) Apparatus 2
under the conditions
5 specified above must additionally exhibit an f2 value 50
compared to a tablet as described in
Example 5 containing the same dose of active pharmaceutical ingredient. In one
embodiment, the
tablet of Example 5 was compacted using a main compaction pressure of 200-290
MPa, more
particularly 240-260 MPa and even more particularly, about 250 MPa.
10 The immediate release tablet of the invention may comprise from 1 to 8
mg (measured as the free
acid) daprodustat or a pharmaceutically acceptable salt thereof which has a
tablet tensile strength of
greater or equal to 1.7 MPa following compaction of the tablet core at a
pressure in the range of 200
to 290 MPa. In more particular embodiments, the tablet tensile strength is
greater than or equal to
1.75, 1.8, 1.9 or 2.0 MPa following compaction of the tablet core at a
pressure in the range of 200 to
15 290 MPa.
In one embodiment, the immediate release tablet of the invention comprises a
compartment
containing daprodustat or a pharmaceutically acceptable salt thereof in an
amount up to 5% based
on the weight of the free acid, where the compartment does not contain a
glidant. In one
embodiment, the compartment contains the non solvated crystalline form of
daprodustat free acid.
In a particular embodiment, the non-solvated crystalline form of daprodustat
free acid is form CS1.
In one embodiment, the tablet is a monolithic tablet consisting of a single
compartment of uniform
composition that is optionally film coated.
In an alternative embodiment, the tablet contains granules dispersed in an
extragranular space and
is optionally film coated. The granular and extragranular compositions may be
different and form
separate compartments. In one embodiment, the granular compartment is the
compartment
containing daprodustat or a pharmaceutically acceptable salt thereof (for
example the non-solvated
crystalline form of daprodustat free acid) and no glidant.
In one embodiment, the intragranular compartment comprises the crystalline
form of non-solvated
daprodustat free acid, a diluent, a binder and a disintegrant and no glidant.
For the avoidance of
doubt, more than one diluent, binder of disintegrant may be included. In one
embodiment, the
intragranular compartment consists of the crystalline form of non-solvated
daprodustat free acid, one
or more diluents, a binder and a disintegrant and no glidant.
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In one embodiment, the extragranular compartment comprises a diluent, a
disintegrant, a lubricant,
and optionally a glidant. For the avoidance of doubt, more than one diluent,
disintegrant, lubricant or
glidant may be included. In one embodiment, the extragranular compartment
consists of one or more
diluents, a disintegrant, a lubricant, and optionally a glidant.
Suitable diluents include lactose, sucrose, dextrose, mannitol, sorbitol,
starch (e.g. corn starch, potato
starch, and pre-gelatinized starch), cellulose and its derivatives (e.g.,
microcrystalline cellulose),
calcium sulfate, and dibasic calcium phosphate. In one embodiment, the diluent
is not lactose.
Suitable binders include starch (e.g., corn starch, potato starch, and pre-
gelatinized starch),
hypromellose, gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar
gum, povidone, and
cellulose and its derivatives (e.g. microcrystalline cellulose).
Suitable disinteg rants include crospovidone, sodium starch glycolate,
croscarmellose sodium, alginic
acid, and sodium carboxymethyl cellulose.
Suitable lubricants include stearic acid, magnesium stearate, calcium
stearate, and talc.
Glidants include colloidal silicon dioxide, talc, starch and magnesium
stearate. In one embodiment,
the glidant is colloidal silicon dioxide or magnesium stearate. In one
embodiment, the glidant is silica.
In one embodiment, the glidant is colloidal silicon dioxide.
In one embodiment, the immediate release tablet consists of:
a) intragranular components comprising the crystalline form of non-solvated
daprodustat free
acid, a diluent, a binder and a disintegrant; and
b) extragranular components comprising a diluent, a disintegrant, a lubricant,
and optionally a
glidant;
wherein the tablet is optionally coated.
In a more particular embodiment, the immediate release tablet consists of:
a) intragranular components consisting of the crystalline form of non-solvated
daprodustat
free acid and one or more diluents, one or more binders and one or more
disintegrants; and
b) extragranular components comprising a diluent, a disintegrant, a lubricant,
and optionally
a glidant;
wherein the tablet is optionally coated.
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A coating may be applied to the tablet core. An example of a commercially
available coating is
"OPADRY 0Y-S-28876 WHITE". Coloured coatings are also commercially available.
In one embodiment, the immediate release tablet contains up to 76 % by weight
of intragranular
components based on the weight of an uncoated tablet.
In one embodiment, the immediate release tablet comprises an intragranular
compartment and an
extragranular compartment wherein:
a. the intragranular components comprise:
i. 1 to 10 mg of the crystalline form of non-solvated daprodustat free acid;
ii. about 5 wt% hypromellose;
iii. about 1.5 wt% croscarnnellose sodium; and
iv. mannitol and microcryrstalline cellulose in a weight ratio from about 2.2
to
about 3.6 (e.g., from about 2.3 to about 3.5, or about 2.25);
b. the extragranular components comprise, based on the total weight of the
extragranular
components:
i. about 12 wt% croscarmellose sodium;
ii. about 4 wt% magnesium stearate;
iii. about 1.5% colloidal silica; and
iv. mannitol and microcryrstalline cellulose in a weight ratio from about 0.3
to about
3 (e.g. about 2).
In a particular embodiment, the tablet comprises about 1, 2 or 4 mg
daprodustat and has a core
tablet weight of about 150 mg. In another embodiment, the tablet comprises
about 6 or 8 mg
daprodustat and has a core tablet weight of about 300 mg. The tablets
described herein may
be optionally film coated.
In one embodiment, the immediate release tablet does not comprise lactose.
MEDICAL USE
The immediate release formulation of the invention may be used in therapy,
more particularly in the
treatment of anemia. In a particular embodiment, the immediate release
formulation of the
invention may be used in the treatment of anemia due to chronic kidney disease
(also known as
renal anemia), anemia in patients with cancer receiving chemotherapy
(including myelosuppressive
or platinum containing chemotherapy), anemia in zidovudine-treated HIV-
infected patients and
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anemia due to rheumatoid arthritis. In one embodiment, the immediate release
formulation of the
invention may be administered to patients receiving elective orthopaedic
surgery.
Accordingly, in one embodiment, the invention provides the immediate release
formulation of the
invention for use in therapy.
In another embodiment, the invention provides the immediate release
formulation of the invention
for use in a method of treating anemia due to chronic kidney disease.
In yet another embodiment, the invention provides use of a composition of
daprodustat or a
pharmaceutically acceptable salt thereof which composition comprises less than
0.15% w/w of a
compound of formula (II) or a pharmaceutically acceptable salt thereofin the
manufacture of the
immediate release formulation of the invention for use in the treatment of
anemia due to chronic
kidney disease.
In another embodiment, the invention provides a method for the treatment of
anemia due to chronic
kidney disease in a subject in need thereof, comprising administering to said
subject the immediate
release formulation of the invention.
Suitably, the subject is a mammal. In a particular embodiment, the subject is
human.
In more particular embodiments, the subject having anemia due to chronic
kidney disease may be
receiving dialysis, for example haemodialysis or peritoneal dialysis. In
another embodiment, the
subject may be iron deficient (TSAT 20% and/or serum ferritin 100 ng/ml)
and additionally
receiving supplemental iron therapy.
In a further embodiment, the invention provides a dosage regimen for the
treatment of anemia due to
chronic kidney disease which aims to maintain haemoglobin in the range 10 to
12 g/dL and provide a
safe increase in haemoglobin levels where haemoglobin levels are below this.
The dose is modified
based on the concentration of haemoglobin determined at clinical visits.
Haemoglobin concentration
may be measured by known methods for example HemoCue.
In one aspect, the invention provides a dosage regimen for the treatment of
anemia due to chronic
kidney disease for patients wherein the immediate release formulation of the
invention is administered
once daily at a dose of either 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 12 mg, 16 mg 0r24
mg and wherein the
dose is increased or decreased by one dose step based on the haemoglobin
concentration of the
patient to maintain the haemoglobin concentration of the patient within the
range 10-12 g/dL. In one
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embodiment, the dose is increased or decreased by one dose step based on the
haemoglobin
concentration of the patient to maintain the haemoglobin concentration of the
patient within the range
10-11 g/dL. In one embodiment, the dose is increased or decreased by one dose
step based on the
haemoglobin concentration of the patient to maintain the haemoglobin
concentration of the patient at
a target of 10 g/dL.
In particular embodiments, the haemoglobin concentration of the patient is
monitored at least once
every three months. In more particular embodiments, the haemoglobin
concentration of the patient is
monitored monthly or every four weeks. The skilled person will appreciate that
monitoring may be
more frequent when treatment is initiated, with the frequency of monitoring
decreasing once the
haemoglobin concentration of the patient has stabilised within the target
range/at the target (10 to 12
g/dL or 10 to 11 g/dL or 10 g/dL).
In embodiments when there is a rapid increase in the haemoglobin concentration
of the patient (e.g.,
exceeding 2.0 g/dL within 4 weeks), the dose is reduced by one dose step or
interrupted.
In embodiments where the haemoglobin concentration of the patient exceeds the
top end of the target
range, the dose is interrupted until the haemoglobin concentration is in
target range, and treatment is
re-started at one dose level lower.
Clinical judgement is also important in dose increases and reductions. In
embodiments where the
patient is above the target range and at risk of thromboembolism (e.g. where a
patient has had a
stroke), the dose is reduced by one dose step or interrupted. In embodiments
where the patient is
exhibiting symptoms of anemia, the dose is increased by one dose step.
In one embodiment, the patient is not on dialysis. In another embodiment, the
patient is on dialysis
(e.g., haemodialysis or peritoneal dialysis).
In embodiments where the patient is not on dialysis and the patient has
previously been treated with
an erythropoiesis stimulating agent (ESA), starting doses are based on prior
ESA dosage. In
embodiments where the patient is not on dialysis and the patient has
previously been treated with an
erythropoiesis stimulating agent (ESA), starting doses are based on the
patient's haemoglobin
concentration. Table 1 sets out suitable starting doses.
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Table 1
Patients Switching from ESA Therapy
Current ESA Dosage
Epoetin alfa Darbepoetin alfa methoxy PEG-epoetin Daprodustat
once daily
IV SC/IV beta SC/IV
(units/week) (mcg/4 week) (mcg /month)
1500 to 2000 20 to 30 30 to 40 1 mg
>2000 to <20,000 >30 to 300 >40 to 360 2 mg
20,000 >300 >360 4 mg
Patients Not Receiving ESA Therapy
Haemoglobin level (g/dL)
<9 4 mg
> 9 2 mg
lESA: Erythropoiesis-stimulating agent
A dosage regimen for treatment of anemia due to chronic kidney disease to
maintain haemoglobin
concentration in the range 10-11 g/dL is provided, wherein the immediate
release tablet of the
5
invention is administered once daily at one of the following doses: 1,2, 4,6,
8, 12, 16 and 24 mg (dose
of free acid), and wherein:
a) where the haemoglobin concentration
12 g/dL, daprodustat therapy is ceased until the
haemoglobin concentration <11.5 g/dL and therapy is commenced at one dose step
lower;
b) where the haemoglobin concentration is in the range
9.5 to < 11.5 g/dL, the dose is
10 maintained;
c) where the haemoglobin concentration is in the range >11 to .1.1.5 g/dL at
two consecutive
clinic visits and there has been an increase or no change in the haemoglobin
concentration
since the last visit, the dose is reduced by one dose step;
d) where the haemoglobin concentration is in the range >11.5 to <12 g/dL and
there has been a
15 decrease in haemoglobin concentration since the last visit, the dose
is maintained;
e) where the haemoglobin concentration is in the range >11.5 to <12 g/dL and
there has been
an increase or no change in the haemoglobin concentration since the last
visit, the dose is
reduced by one dose step;
f) where the haemoglobin concentation is in the range .9.5 to <10 at two
consecutive clinic visits
20 and
there has been a decrease or no change in the haemoglobin concentration since
the last
visit, the dose is increased by one dose step;
g) where the haemoglobin concentration is in the range 7.5 to <9.5 g/dL and
there has been an
increase in haemoglobin concentration of .10.5 g/dL since the last visit, the
dose is maintained;
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h) where the haemoglobin concentration is in the range 7.5 to <9.5 g/dL and
there has been a
decrease, no change or an increase of <0.5 g/dL in haemoglobin concentration
since the last visit,
the dose is increased by one dose step;
i) where the haemoglobin concentration is <7.5 g/dL, the dose is increased
by one dose step;
j) where there has been an increase in haemoglobin concentration of >2 g/dL
over 4 weeks, or
an increase in haemoglobin concentration of >1 g/dL over 2 weeks, the dose is
reduced by one
dose step; and
k) where there has been a decrease in haemoglobin concentration of >2 g/dL
over 4 weeks, or a
decrease in haemoglobin concentration of >1 g/dL over 2 weeks, the dose is
increased by one
dose step.
In one embodiment, the invention provides the immediate release formulation of
the invention for
use in the treatment of anemia due to chronic kidney disease, wherein the
immediate release tablet
of the invention is administered once daily at one of the following doses: 1,
2, 4, 6, 8, 12, 16 and 24
mg (dose of free acid) in accordance with a dosage regimen as described
herein.
In one embodiment, the invention provides use of a composition of daprodustat
or a
pharmaceutically acceptable salt thereof which composition comprises less than
0.15% w/w of a
compound of formula (II) or a pharmaceutically acceptable salt thereof in the
manufacture of the
immediate release formulation of the invention for use in the treatment of
anemia due to chronic
kidney disease, wherein the immediate release formulation of the invention is
administered once
daily at one of the following doses: 1, 2, 4, 6, 8, 12, 16 and 24 mg (dose of
free acid) in accordance
with a dosage regimen as described herein.
In one aspect, the invention provides a dosage regimen for the treatment of
anemia due to chronic
kidney disease for patients on dialysis wherein the immediate release
formulation of the invention is
administered three times per week with each dose being either 2 mg, 4 mg, 8
mg, 12 mg, 16 mg, 24
mg, 32 mg or 48 mg and wherein the dose is increased or decreased by one dose
step based on the
haemoglobin concentration of the patient to maintain the haemoglobin
concentration of the patient
within the range 10-12 g/dL. In one embodiment, the dose is increased or
decreased by one dose
step based on the haemoglobin concentration of the patient to maintain the
haemoglobin concentration
of the patient within the range 10-11 g/dL.
In particular embodiments, the haemoglobin concentration of the patient is
monitored at least once
every three months. In more particular embodiments, the haemoglobin
concentration of the patient is
monitored monthly or every four weeks. The skilled person will appreciate that
monitoring may be
more frequent when treatment is initiated, with the frequency of monitoring
decreasing once the
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haemoglobin concentration of the patient has stabilised within the target
range (1010 12 g/dL or 10 to
11 g/dL).
In embodiments when there is a rapid increase in the haemoglobin concentration
of the patient (e.g.,
exceeding 2.0 g/dL within 4 weeks), the dose is reduced by one dose step or
interrupted.
In embodiments where the haemoglobin concentration of the patient exceeds the
top end of the target
range, the dose is interrupted until the haemoglobin concentration is in
target range, and treatment is
re-started at one dose level lower.
Clinical judgement is also important in dose increases and reductions. In
embodiments where the
patient is above the target range and at risk of thromboembolism (e.g. where a
patient has had a
stroke), the dose is reduced by one dose step or interrupted. In embodiments
where the patient is
exhibiting symptoms of anemia, the dose is increased by one dose step.
In embodiments where the patient is on dialysis and the patient has previously
been treated with an
erythropoiesis stimulating agent (ESA), starting doses are based on prior ESA
dosage. Table 2 sets
out suitable starting doses.
Table 2
Current ESA Dosage Daprodustat Dose
Epoetin alfa Darbepoetin alfa methoxy PEG-epoetin Once
daily Three-times
IV SC/IV beta SC/IV per
vveek2
(units/week) (mcg/4 week) (mcg /month)
<1500 (This dose 2 mg
level is not agreed
yet)
1500 to 2000 20 to 30 30 to 40 4 mg 8 mg
>2000 to <10000 >30 to 150 >40 to 180 6 mg 12 mg
10,000 to <20,000 >150 to 300 >180 to 360 8 mg 16 mg
20,000 >300 >360 12 mg 24 mg
lESA: Erythropoiesis-stimulating agent
2Haemodialysis patients only
Table 3 sets out suitable starting doses for patients initiating dialysis not
currently treated with an
erythropoiesis stimulating agent (ESA).
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Table 3
Haemoglobin level (g/dL) Daprodustat once daily
<9 4 mg
to 10 2 mg
>10 1 mg
1Patients initiating dialysis includes patients in whom dialysis is planned to
start in the next
6 weeks, or those who have started dialysis in the last 3 months.
2ESA: Erythropoiesis-stimulating agent
A dosage regimen for treatment of anemia due to chronic kidney disease to
maintain haemoglobin
concentration in the range 10-11 g/dL is provided, wherein the immediate
release tablet of the
invention is administered three times per week with each dose being either 2
mg, 4 mg, 8 mg, 12 mg,
16 mg, 24 mg, 32 mg or 48 mg (dose of free acid), and wherein:
a) where the haemoglobin concentration
12 g/dL, daprodustat therapy is ceased until the
haemoglobin concentration <11.5 g/dL and therapy is commenced at one dose step
lower;
b) where the haemoglobin concentration is in the range 9.5 to < 11.5 g/dL,
the dose is
maintained;
C) where the haemoglobin concentration is in the range >11 to 1.1.5 g/dL at
two consecutive
clinic visits and there has been an increase or no change in the haemoglobin
concentration
since the last visit, the dose is reduced by one dose step;
d) where the haemoglobin concentration is in the range >11.5 to <12 g/dL and
there has been a
decrease in haemoglobin concentration since the last visit, the dose is
maintained;
e) where the haemoglobin concentration is in the range >11.5 to <12 g/dL and
there has been
an increase or no change in the haemoglobin concentration since the last
visit, the dose is
reduced by one dose step;
f) where the haemoglobin concentation is in the range ?9.5 to <10 at two
consecutive clinic visits
and there has been a decrease or no change in the haemoglobin concentration
since the last
visit, the dose is increased by one dose step;
g) where the haemoglobin concentration is in the range 7.5 to <9.5 g/dL and
there has been an
increase in haemoglobin concentration of Ø5 g/dL since the last visit, the
dose is maintained;
h) where the haemoglobin concentration is in the range 7.5 to <9.5 g/dL and
there has been a
decrease, no change or an increase of <0.5 g/dL in haemoglobin concentration
since the last visit,
the dose is increased by one dose step;
i) where the haemoglobin concentration is <7.5 g/dL, the dose is increased
by one dose step;
j) where there has been an increase in haemoglobin concentration of >2 g/dL
over 4 weeks, or
an increase in haemoglobin concentration of >1 g/dL over 2 weeks, the dose is
reduced by one
dose step; and
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k) where there has been a decrease in haemoglobin concentration of >2 g/dL
over 4 weeks, or a
decrease in haemoglobin concentration of >1 g/dL over 2 weeks, the dose is
increased by one
dose step.
In one embodiment, the invention provides the immediate release formulation of
the invention for
use in the treatment of anemia due to chronic kidney disease in patients on
dialysis, wherein the
immediate release formulation of the invention is administered three times per
week with each dose
being either: 2 mg, 4 mg, 8 mg, 12 mg, 16 mg, 24 mg, 32 mg or 48 mg (dose of
free acid) in
accordance with a dosage regimen as described herein.
In one embodiment, the invention provides provides a composition of
daprodustat or a
pharmaceutically acceptable salt thereof which composition comprises less than
0.15% w/w of a
compound of formula (II) or a pharmaceutically acceptable salt thereof in the
manufacture of the
immediate release formulation of the invention for use in the treatment of
anemia due to chronic
kidney disease in patients on dialysis, wherein the immediate release
formulation of the invention is
administered three times per week with each dose being either: 2 mg, 4 mg, 8
mg, 12 mg, 16 mg, 24
mg, 32 mg or 48 mg (dose of free acid) in accordance with a dosage regimen as
described herein.
For the avoidance of doubt, it is noted that any particular dose can be
administered in a single
dosage form or multiple dosage forms. For example, the dose of 8 mg could be
administered as a
single 8 mg dosage form, or two 4 mg dosage forms, or four 2 mg dosage forms
or eight 1 mg
dosage forms, or a 6 mg and a 2 mg dosage form.
It will be apparent that dose adjustments will result in the daprodustat dose
being increased or
decreased by one dose step at a time. Those receiving the highest (maximum)
dose of daprodustat
who require a dose increase will maintain the same dose, while those receiving
the lowest dose of
daprodustat that require a dose decrease will finish daprodustat therapy.
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EXAMPLES
Example 1
Daprodustat is prepared according to the general synthetic scheme supra in a
route comprising
Stages 1, 2a, 2b, 2c and 3 wherein P' is ethyl and the metal ion is a
potassium ion. The impact of
5 impurities derived from Stage 1 of the process on drug substance quality
was assessed by
determining their purging when intentionally added to the Stage 2/3 process.
In a first experiment,
impurities generated in Stage 1 (N-cyclohexyl-N-
(cyclohexylcarbamoyl)acetamide, 3-(1,3-
dicyclohexylureido)-3-oxopropanoic acid, 5-acetyl-1,3-dicyclohexylpyrimidine-
2,4,6(1H,3H,5H)-trione
and 1,3-dicyclohexy1-2H-pyrano[2,3-d]pyrimidine-2,4,5,7(1H,3H,6H)-tetraone)
and Stage 1 starting
10 materials (1,3-dicyclohexylurea and malonic acid) were each spiked at a
level of 0.3% w/w in a
group into the Stage 1 product 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-
trione and this was used
to produce daprodustat. The levels of each of the spiked materials were
identified in daprodustat by
HPLC analysis. The only spiked material detectable in daprodustat was 5-acetyl-
1,3-
dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione which was present in daprodustat
at a level of 0.8
15 w/w.
In a second experiment, 0.5% acetic acid was spiked into the Stage 1 product
1,3-
dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione and this was used to produce
daprodustat. This
resulted in the presence of 5-acetyl-1,3-dicyclohexylpyrimidine-
2,4,6(1H,3H,5H)-trione at a level of
20 0.09 w/w in daprodustat.
Further studies were performed to determine the impact on drug substance
quality, if residual 5-
acetyl-1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione and acetic acid were
simultaneously present
in 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione (Table 4). Firstly, the
impurities were spiked into
25 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione independently to
quanitfy their individual impact.
5-acetyl-1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione, when added alone,
was confirmed to
carry over to daprodustat. Addition of acetic acid at a reduced level caused
low but detectable
formation of 5-acetyl-1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione.
Simultaneous spiking of 5-
acetyl-1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione and acetic acid
confirmed their synergistic
impact on the drug substance.
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Table 4
Additive Level 5-acetyl-1,3-
dicyclohexylpyrimidine-
(w/w) 2,4,6(1H,3H,5H)-trione present
in daprodustat
(%w/w)
5-acetyl-1,3- 0.3% 0.21%
dicyclohexylpyrimidine-
2,4,6(1H,3H,51-1)-trione
Acetic acid 0.15%
5-acetyl-1,3- 0.09% 0.12%
dicyclohexylpyrimidine-
2,4,6(1H,3H,5H)-trione
Acetic acid 0.15%
5-acetyl-1,3- 0.07% 0.11%
dicyclohexylpyrimidine-
2,4,6(1H,3H,5H)-trione
Acetic acid 0.1%
This series of experiments demonstrates that levels of 5-acetyl-1,3-
dicyclohe)Mpyrimidine-
2,4,6(1H,3H,5H)-trione and acetic acid going into Stage 2 needs to be
controlled in order to keep
levels of 5-acetyl-1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione below
0.15% in drug product.
Levels of 0.1% acetic acid can be tolerated in Stage 2 where levels of 5-
acetyl-1,3-
dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione are also controlled.
Example 2
Stage 1 comprises reaction of 1,3-dicyclohexylurea and malonic acid in the
presence of the
dehydrating agent acetic anhydride in acetic acid. The reaction proceeds via
an intermediate, 341,3-
dicyclohexylureido)-3-oxopropanoic acid. The impact of imidazole on the rate
of formation of the
desired product and impurities was studied by spiking imidazole at 0.5% w/w in
1,3-dicyclohexylurea.
The reaction profile was determined at 6 and 8 h by HPLC analysis of the
filtered reaction mixture.
Imidazole significantly increased the rate of intermediate consumption (Figure
1A) and formation of
the product-derived impurities (5-acetyl-1,3-dicyclohexylpyrimidine-
2,4,6(1H,3H,5H)-trione (Figure
1D) and 1,3-dicyclohexy1-2H-pyrano[2,3-d]pyrimidine-2,4,5,7(1H,3H,6H)-tetraone
(Figure 1C)) whilst
reducing formation of the 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione
product (Figure 18),
leading to conversion of the majority of 1,3-dicyclohexylpyrimidine-
2,4,6(1H,3H,5H)-trione to a
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mixture of 5-acetyl-1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione and 1,3-
dicyclohexy1-2H-
pyrano[2,3-d]pyrimidine-2,4,5,7(1H,3H,6H)-tetraone. The mechanism by which
added imidazole
causes acceleration of these reactions was inferred from the similarity of the
reaction profile when
adding exogenous N,N'-dimethylaminopyridine (Figure 2); both acting as
nucleophilic catalysts for the
series of condensation reactions occurring in this stage. A study of the
reaction progress with varying
levels of imidazole added to 1,3-dicyclohexylurea (Figure 3) showed
acceleration of the reaction at
loadings as low as 0.05%.
Example 3
1,3-Dicyclohendurea is converted to 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-
trione by treatment
with acetic anhydride in acetic acid. Preliminary studies including the study
reported in Example 1
showed that 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione slowly reacts
with acetic anhydride as
it forms in Stage 1 to give impurity, 5-acetyl-1,3-dicyclohexylpyrimidine-
2,4,6(1H,3H,5H)-trione. A
screening Design of Experiment (DoE) was conducted to identify parameters and
attributes linked to
the formation of 5-acetyl-1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione.
The study was a two
level, six factor, 20 run fractional factorial design with 4 centre points.
The parameters and ranges
studied are shown in Table 5:
Table 5
Parameter Low Level Centre Point High Level Units
Quantity of acetic 2.0 3.0 4.0 Volumes
acid
Quantity of 1.1 1.2 1.3 Molar
equivalents
malonic acid
Quantity of acetic 5.0 6.0 7.0 Molar
equivalents
anhydride
Reaction 50 55 60 C
temperature
Imidazole content 0.013 0.26 0.5 % w/w
in 1,3-
dicyclohexylurea
Power input (at 24 228 802 W/m3
impeller speed) (150 rpm) (325 rpm) (500 rpm)
The rate of formation of 5-acetyl-1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-
trione was the response
studied. Time course data were collected to determine the initial rate of 5-
acetyl-1,3-
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dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione formation under each condition.
Samples of the
reaction filtrate were taken at regular intervals, and the relative content of
1,3-dicyclohexylpyrimidine-
2,4,6(1H,3H,5H)-trione and 5-acetyl-1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-
trione in the filtrate
was determined by HPLC. The data for each condition were fitted to a second
order polynomial
equation to describe the reaction progress. The equation was solved to
determine the time when 15%
conversion was reached. The initial rate of 5-acetyl-1,3-
dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione
is inverse of this time.
Analysis of the screening study is presented using the half-normal plot in
Figure 4. The imidazole
content in 1,3-dicyclohexylurea was found to have a significant (P <0.0001)
impact on the rate of 5-
acetyl-1,3-dicyclohendpyrimidine-2,4,6(1H,3H,5H)-trione formation. Reaction
temperature (P =
0.0003) and the quantity of acetic acid (P= 0.0016) also showed effects.
The impact of changes to the quantity of imidazole in 1,3-dicyclohexylurea in
combination with
quantity of acetic acid or reaction temperature is shown in the interaction
plots (Figure 5). These plots
indicate that high quantities of imidazole in 1,3-dicyclohexylurea, in
combination with either high
reaction temperature or low quantity of acetic acid, resulting in increased
reaction concentration,
accelerate the formation of 5-acetyl-1,3-dicyclohexylpyrimidine-
2,4,6(1H,3H,5H)-trione.
Example 4
Examples 2 and 3 show that the formation of 5-acetyl-1,3-
dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-
trione in Stage 1 is dependent on the presence of imidazole in 1,3-
dicyclohexylurea and also the
quantity of acetic acid and reaction temperature. Example 1 additionally shows
that 5-acetyl-1,3-
dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione cannot be readily purged in
later stages. An
assessment of the purging capability of the step of isolating the Stage 1
product was performed to
establish tolerable limits for this impurity at the end of Stage 1.
The solubility of 5-acetyl-1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione
was measured in 29.5%
v/v acetic anhydride¨acetic acid (a mimic for the solvent composition at the
end of Stage 1), acetic
acid and water. The solubility was measured by saturation of the solvent with
the component, filtration
and determination of the component concentration in the supernatant. The
solubility of 5-acetyl-1,3-
dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione in 29.5%v/v acetic
anhydride¨acetic acid at 15 C was
determined to be 43.7 mg/ml. The solubility of 5-acetyl-1,3-
dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-
trione in acetic acid at 20 C was determined to be 62.3 mg/ml and the
solubility of 5-acetyl-1,3-
dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione in water at 25 C was determined
to be <0.1 mg/ml.
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A spiking study was performed to determine the purging of 5-acetyl-1,3-
dicyclohexylpyrimidine-
2,4,6(1H,3H,5H)-trione during isolation of the Stage 1 product, 1,3-
dicyclohexylpyrimidine-
2,4,6(1H,3H,5H)-trione. 5-acetyl-1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-
trione was added to a
suspension of 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione in 29.5%
acetic anhydride¨acetic
acid. The level of 5-acetyl-1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione
following filtration at 15
C and washing with acetic acid (2 x 1.0 volumes), followed by water (2 x 1.0
volumes) is shown in
Table 6.
Table 6
Additive Amount added Amoun Level in filtrate Isolated
1,3-
relative to 1,3- t relative to 1,3-
dicyclohexylpyrimidi
dicyclohexylpyrimidi relative dicyclohexylpyrimidi ne-
ne- to ne-
2,4,6(1H,3H,5H)-
2,4,6(1H,3H,5H)- solvent 2,4,6(1H,3H,5H)- trione purity (%
trione. (% w/w) (mg/m trione (% area at w/w)
L) 210 nm)
5-acetyl-1,3-
dicyclohexylpyrimidi
ne- 19.8 45.2 75.8 100.0
2,4,6(1H,3H,5H)-
trione
Process stretching studies were performed to demonstrate the purging of 5-
acetyl-1,3-
dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione at larger scale. The Stage 1
reaction was conducted
with the conditions set out in Table 7, that are predicted to generate
elevated 5-acetyl-1,3-
dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione followed by filtration at 15 C
and washing with acetic
acid (2 x 1.0 volumes), followed by water (2 x 1.0 volumes).
Table 7
Reaction conditions
Quantity of 1,3-dicyclohexylurea (Molar equivalents) 1.0
Quantity of acetic acid (Volumes) 2.7
Quantity of malonic acid (Molar equivalents) 1.3
Quantity of acetic anhydride (Molar equivalents) 6.6
Quantity of imidazole in 1,3-dicyclohmlurea (% w/w) 0.15
Reaction temperature ( C) 60
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HPLC of the filtrate showed that the % area relative to the reaction product,
1,3-dicyclohexylpyrimidine-
2,4,6(1H,3H,5H)-trione, was 45.6. The purity of 1,3-dicyclohexylpyrimidine-
2,4,6(1H,3H,5H)-trione
(% area) was 100% with less than < 0.5% (% area) total impurities.
5 Example 5
Tablet formulations of daprodustat free acid may be prepared as follows. The
tablet cores comprise
granules and extragranular components. Granules are prepared by adding
daprodustat, mannitol,
microcrystalline cellulose, hypromellose 2910 and croscarmellose sodium into a
high shear
granulator. The powders are blended under high shear for at least 5 minutes
and granulation
10 performed while spraying at least 26% w/w purified water over a water
addition time of at least 7
minutes and wet massing time of at least 2 minutes. The wet granules are dried
in a fluid bed dryer
to a target moisture content of not exceeding 2%w/w at a product temperature
of at least 380C and
the granules are dry milled to normalize granule size distribution. The milled
granules are futher
blended with extragranular components man nitol, microcrystalline cellulose,
croscarmellose sodium
15 and glidant colloidal silicon dioxide. Magnesium stearate is added and
the resulting mixture is
compressed using compaction pressures in the range 180 to 370 MPa into tablet
cores using a
rotary tablet press under the following conditions.
Tablet shape / size: round, biconvex tablets / 7mm diameter (4mg); 9mm
diameter (6mg)
20 Compression speed of at least 40000 tablets per hour
The compositions of the tablets are provided in Table 8.
Table 8
Component Quantity (mg/tablet)
1 mg 2 mg 4 mg 6 mg 8 mg
Granules
Daprodustat 1.00 2.00 4.00 6.00 8.00
Mannitol 72.30 71.60 70.22 141.83 140.45
Microcrystalline Cellulose 31.88 31.58 30.96 62.54
61.92
Hypromellose 2910 5.63 5.63 5.63 11.25
11.25
Croscarmellose Sodium 1.69 1.69 1.69 3.38 3.38
Purified Water - - -
Extragranular Components
Mannitol 20.44 20.44 20.44 40.87
40.87
Microcrystalline Cellulose 10.50 10.50 10.50 21.00
21.00
Croscarmellose Sodium 4.50 4.50 4.50 9.00 9.00
Colloidal Silicon Dioxide 0.56 0.56 0.56 1.13 1.13
Magnesium Stearate 1.50 1.50 1.50 3.00 3.00
Core tablet weight
150.0 300.0
(m9)
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Purified water for granulation is removed during processing and does not
remain in the tablet.
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